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Midbrain Dopamine Controls Anxiety-like Behavior by Engaging Unique Interpeduncular Nucleus Microcircuitry

  • Steven R. DeGroot
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts

    Graduate Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Rubing Zhao-Shea
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Leeyup Chung
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Paul M. Klenowski
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Fangmiao Sun
    Affiliations
    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China

    PKU-IDG/McGovern Institute for Brain Research, Beijing, China
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  • Susanna Molas
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Paul D. Gardner
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Yulong Li
    Affiliations
    State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China

    PKU-IDG/McGovern Institute for Brain Research, Beijing, China

    Peking-Tsinghua Center for Life Sciences, Beijing, China
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  • Andrew R. Tapper
    Correspondence
    Address correspondence to Andrew R. Tapper, Ph.D.
    Affiliations
    Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts
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      Abstract

      Background

      Dopamine (DA) is hypothesized to modulate anxiety-like behavior, although the precise role of DA in anxiety behaviors and the complete anxiety network in the brain have yet to be elucidated. Recent data indicate that dopaminergic projections from the ventral tegmental area (VTA) innervate the interpeduncular nucleus (IPN), but how the IPN responds to DA and what role this circuit plays in anxiety-like behavior are unknown.

      Methods

      We expressed a genetically encoded G protein–coupled receptor activation–based DA sensor in mouse midbrain to detect DA in IPN slices using fluorescence imaging combined with pharmacology. Next, we selectively inhibited or activated VTA→IPN DAergic inputs via optogenetics during anxiety-like behavior. We used a biophysical approach to characterize DA effects on neural IPN circuits. Site-directed pharmacology was used to test if DA receptors in the IPN can regulate anxiety-like behavior.

      Results

      DA was detected in mouse IPN slices. Silencing/activating VTA→IPN DAergic inputs oppositely modulated anxiety-like behavior. Two neuronal populations in the ventral IPN (vIPN) responded to DA via D1 receptors (D1Rs). vIPN neurons were controlled by a small population of D1R neurons in the caudal IPN that directly respond to VTA DAergic terminal stimulation and innervate the vIPN. IPN infusion of a D1R agonist and antagonist bidirectionally controlled anxiety-like behavior.

      Conclusions

      VTA DA engages D1R-expressing neurons in the caudal IPN that innervate vIPN, thereby amplifying the VTA DA signal to modulate anxiety-like behavior. These data identify a DAergic circuit that mediates anxiety-like behavior through unique IPN microcircuitry.
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      Linked Article

      • Dopamine Release in the Midbrain Promotes Anxiety
        Biological PsychiatryVol. 88Issue 11
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          The mesolimbic dopamine system is at the center of information processing and sends projections throughout the brain that have been linked to reward, motivation, salience, novelty, and the regulation of affective states (1). This system has been a major focus of psychiatric disease research given the critical role it plays in mood disorders—including anxiety disorders, where its dysregulation has been linked to the expression of negative affective states in human and animal models (2,3). Therefore, a significant effort has focused on understanding how the dopamine system encodes information and how dopamine projections balance competing information to drive the expression of adaptive and maladaptive behaviors.
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